The Intestinal Microbiome Restricts Alphavirus Infection and Dissemination through a Bile Acid-Type I IFN Signaling Axis

Emma S. Winkler, Swathi Shrihari, Barry L. Hykes, Scott A. Handley, Prabhakar S. Andhey, Yan Jang S. Huang, Amanda Swain, Lindsay Droit, Kranthi K. Chebrolu, Matthias Mack, Dana L. Vanlandingham, Larissa B. Thackray, Marina Cella, Marco Colonna, Maxim N. Artyomov, Thaddeus S. Stappenbeck, Michael S. Diamond

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Chikungunya virus (CHIKV), an emerging alphavirus, has infected millions of people. However, the factors modulating disease outcome remain poorly understood. Here, we show in germ-free mice or in oral antibiotic-treated conventionally housed mice with depleted intestinal microbiomes that greater CHIKV infection and spread occurs within 1 day of virus inoculation. Alteration of the microbiome alters TLR7-MyD88 signaling in plasmacytoid dendritic cells (pDCs) and blunts systemic production of type I interferon (IFN). Consequently, circulating monocytes express fewer IFN-stimulated genes and become permissive for CHIKV infection. Reconstitution with a single bacterial species, Clostridium scindens, or its derived metabolite, the secondary bile acid deoxycholic acid, can restore pDC- and MyD88-dependent type I IFN responses to restrict systemic CHIKV infection and transmission back to vector mosquitoes. Thus, symbiotic intestinal bacteria modulate antiviral immunity and levels of circulating alphaviruses within hours of infection through a bile acid-pDC-IFN signaling axis, which affects viremia, dissemination, and potentially transmission.

Original languageEnglish
Pages (from-to)901-918.e18
JournalCell
Volume182
Issue number4
DOIs
StatePublished - Aug 20 2020

Keywords

  • Clostridium
  • alphavirus
  • bile acid
  • chikungunya
  • interferon
  • microbiome
  • monocyte
  • pathogenesis
  • plasmacytoid dendritic cell

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